Post-translational Modifications of OLIG2 Regulate Glioma Invasion through the TGF-β Pathway

• Published in: Cell reports (Cambridge) Vol. 16; no. 4; pp. 950 - 966
• Main Authors: Singh, Shiv K., Fiorelli, Roberto, Kupp, Robert, Rajan, Sindhu, Szeto, Emily, Lo Cascio, Costanza, Maire, Cecile L., Sun, Yu, Alberta, John A., Eschbacher, Jennifer M., Ligon, Keith L., Berens, Michael E., Sanai, Nader, Mehta, Shwetal
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.07.2016; Elsevier
• Subjects: Animals; Cell Line, Tumor; Cell Proliferation - genetics; Glioblastoma - genetics; Glioblastoma - pathology; Humans; Hyaluronan Receptors - genetics; Mice; Mice, Nude; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; Oligodendrocyte Transcription Factor 2 - genetics; Phosphorylation - genetics; Protein Processing, Post-Translational - genetics; Signal Transduction - genetics; Transforming Growth Factor beta - genetics; Zinc Finger E-box-Binding Homeobox 1 - genetics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.06.045

In glioblastoma, invasion and proliferation are presumed to be mutually exclusive events; however, the molecular mechanisms that mediate this switch at the cellular level remain elusive. Previously, we have shown that phospho-OLIG2, a central-nervous-system-specific transcription factor, is essential for tumor growth and proliferation. Here, we show that the modulation of OLIG2 phosphorylation can trigger a switch between proliferation and invasion. Glioma cells with unphosphorylated OLIG2S10, S13, S14 are highly migratory and invasive, both in vitro and in vivo. Mechanistically, unphosphorylated OLIG2 induces TGF-β2 expression and promotes invasive mesenchymal properties in glioma cells. Inhibition of the TGF-β2 pathway blocks this OLIG2-dependent invasion. Furthermore, ectopic expression of phosphomimetic Olig2 is sufficient to block TGF-β2-mediated invasion and reduce expression of invasion genes (ZEB1 and CD44). Our results not only provide a mechanistic insight into how cells switch from proliferation to invasion but also offer therapeutic opportunities for inhibiting dissemination of gliomas. [Display omitted] •Glioma cells expressing unphosphorylated OLIG2 are highly invasive•Unphosphorylated OLIG2 upregulates the TGF-β2 pathway and activates invasion genes•Inhibition of the TGF-β pathway blocks OLIG2-mediated invasion•Phospho-OLIG2 suppresses TGF-β2-mediated invasion Singh et al. show that the phosphorylation status of a CNS-specific transcription factor, OLIG2, dictates the switch from the proliferative to invasive phenotype in glioblastoma. Unphosphorylated OLIG2 induces invasion through upregulation of the TGF-β2 pathway. The authors provide a putative mechanism through which OLIG2 regulates both proliferation and invasion in GBM cells.